Angiogenesis Activator Is Target of Anticancer Drugs

The molecular basis for the inducement of angiogenesis has been determined. By unraveling the structure of the "alpha” domain of an activator protein called hypoxia inducing factor (HIF-1) in complex with its "coactivator” protein called CBP, researchers have paved the way for the development of anticancer drugs that would work by limiting the access of tumors to the blood supply. The findings were reported in the April 16, 2002, issue of The Proceedings of the National Academy of Sciences.

Normally when tissues are starved of oxygen, they activate genes that induce angiogenesis to bring more oxygen-rich blood to cells that need it. This increased blood supply allows cells to survive oxygen deprivation. The HIF-1/CBP complex is the operative result of this type of gene activation. Expanding tumors also use this mechanism to provide the blood they need for growth. Blocking angiogenesis can cause tumors to regress, and it is believed that specific drugs designed for this purpose might produce milder side effects than general chemotherapy.


Scientists from Scripps Research Institute (La Jolla, CA, USA) have accomplished the critical first step of describing the molecular interaction between the components of the HIF-1/CBP complex. Their work reveals that the addition of a hydroxy (-OH) group to a single asparagines amino acid within the contact region can completely disrupt the complex.

"This provides a starting point for the design of antitumor agents,” says Dr. Maria Martinez-Yamout, one of the paper's lead authors. "These agents would, for example, mimic the effect of the hydroxy addition and block the activity of HIF-1 in cancerous cells.”

Lacking the ability to grow new blood vessels and increase their supply of oxygen, the cancerous cells would not be able to continue dividing, and tumor growth would stop.




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